Organophosphorus Flame Retardant TPP-Induced Human Corneal Epithelial Cell Apoptosis through Caspase-Dependent Mitochondrial Pathway.

A widely used organophosphate flame retardant (OPFR), triphenyl phosphate (TPP), is frequently detected in various environmental media and humans. However, there is little known on the human corneal epithelium of health risk when exposed to TPP. In this study, human normal corneal epithelial cells (HCECs) were used to investigate the cell viability, morphology, apoptosis, and mitochondrial membrane potential after they were exposed to TPP, as well as their underlying molecular mechanisms. We found that TPP decreased cell viability in a concentration-dependent manner, with a half maximal inhibitory concentration (IC50) of 220 µM. Furthermore, TPP significantly induced HCEC apoptosis, decreased mitochondrial membrane potential in a dose-dependent manner, and changed the mRNA levels of the apoptosis biomarker genes (Cyt c, Caspase-9, Caspase-3, Bcl-2, and Bax). The results showed that TPP induced cytotoxicity in HCECs, eventually leading to apoptosis and changes in mitochondrial membrane potential. In addition, the caspase-dependent mitochondrial pathways may be involved in TPP-induced HCEC apoptosis. This study provides a reference for the human corneal toxicity of TPP, indicating that the risks of OPFR to human health cannot be ignored.

Manganese-based nanomaterials promote synergistic photo-immunotherapy: green synthesis, underlying mechanisms, and multiple applications.

Single phototherapy and immunotherapy have individually made great achievements in tumor treatment. However, monotherapy has difficulty in balancing accuracy and efficiency. Combining phototherapy with immunotherapy can realize the growth inhibition of distal metastatic tumors and enable the remote monitoring of tumor treatment. The development of nanomaterials with photo-responsiveness and anti-tumor immunity activation ability is crucial for achieving photo-immunotherapy. As immune adjuvants, photosensitizers and photothermal agents, manganese-based nanoparticles (Mn-based NPs) have become a research hotspot owing to their multiple ways of anti-tumor immunity regulation, photothermal conversion and multimodal imaging. However, systematic studies on the synergistic photo-immunotherapy applications of Mn-based NPs are still limited; especially, the green synthesis and mechanism of Mn-based NPs applied in immunotherapy are rarely comprehensively discussed. In this review, the synthesis strategies and function of Mn-based NPs in immunotherapy are first introduced. Next, the different mechanisms and leading applications of Mn-based NPs in immunotherapy are reviewed. In addition, the advantages of Mn-based NPs in synergistic photo-immunotherapy are highlighted. Finally, the challenges and research focus of Mn-based NPs in combination therapy are discussed, which might provide guidance for future personalized cancer therapy.

Loss of RPA1 Impairs Peripheral T Cell Homeostasis and Exacerbates Inflammatory Damage through Triggering T Cell Necroptosis.

The peripheral T cell pool is maintained at dynamic homeostasis through fine-tuning of thymic output and self-renewal of naïve T cells. Lymphopenia or reduced lymphocyte number is implicated in autoimmune diseases, yet little is known about the homeostatic mechanisms. Here, it is reported that the replication protein A1 (RPA1) plays a critical role in T cell homeostasis. Utilizing T cell-specific Rpa1-deficient (Rpa1fl/fl Cd4-cre) mice, loss of Rpa1 results in lymphopenia through restraining peripheral T cell population and limiting TCR repertoire diversity. Moreover, Rpa1fl/fl Cd4-cre mice exhibit increased susceptibility to inflammatory diseases, including colitis and hepatitis. Clinical analysis reveals that the expression of RPA1 is reduced in patients with ulcerative colitis or other autoinflammatory diseases. Mechanistically, depletion of RPA1 activates ZBP1-RIPK3 signaling through triggering the genomic DNA leakage into cytosol, consequently resulting in T cell necroptosis. This necroptotic T cell death induced by RPA1 deficiency allows the release of damage-associated molecular patterns (DAMPs), which in turn recruits leukocytes and exacerbates inflammatory response. Reciprocally, chemical or genetic inhibition of necroptosis signaling can ameliorate the Rpa1 deficiency-induced inflammatory damage. The studies thus uncover the importance of RPA1-ZBP1-RIPK3 axis in T cell homeostasis and provide a promising strategy for autoinflammatory disease treatment.

Global Spread Dynamics and Intrinsic Evolutionary Dynamics of Apple Chlorotic Leaf Spot Virus Whole-Genome Sequences over the Last 30 Years.

Apple chlorotic leaf spot virus (ACLSV; genus Trichovirus) is an economically important virus. Approximately 101 ACLSV whole-genome sequences were obtained from NCBI and used to explore the evolutionary dynamics of ACLSV. The time to the most recent common ancestor of ACLSV based on BEAST analysis appeared on an apple host from Canada in 1918 and then spread around the world in three ways concurrent with host spread. The maximum clade credibility tree of ACLSV shows that the mean evolution rate was 4.92 × 10-4 substitutions per site per year (subs/site/year), and we found that, during host evolution, the rate of evolution was mostly 2.31 × 10-4 to 2.72 × 10-4 subs/site/year. The rate of geographic evolution was 5.51 × 10-4 to 6.17 × 10-4 subs/site/year. To further explore the intrinsic changes in ACLSV during the process of geographic and host spread, we explored the secondary structural changes of the ACLSV coat protein (CP), which were mainly concentrated in four regions-20 to 40, 70 to 90, 120 to 140, and 180 to 193-which are related to the presence or absence and change in length of the ß-turn, ß strand, coil, and α helix, respectively. We then explored the codon usage preference within the CP across the migration pathways of ACLSV. These comprehensive analyses not only reveal the changes in ACLSV in the last 30 years but also further elucidate the intrinsic evolutionary dynamics of ACLSV. This is also the first report on the intrinsic evolutionary dynamics of ACLSV.

Spatially Dependent Electronic Structures and Excitons in a Marginally Twisted Moiré Superlattice of Spiral WS2.

Twisted two-dimensional transition metal dichalcogenide (TMD) moiré superlattices provide an additional degree of freedom to engineer electronic and optical properties. Nevertheless, controllable synthesis of marginally twisted homo TMD moiré superlattices is still a challenge. Here, physical vapor deposition grown spiral WS2 nanosheets are demonstrated to be a marginally twisted moiré superlattice using scanning tunneling microscopy and spectroscopy. Periodic moiré superlattices are found on the third layer (3L) and 4L of the spiral WS2 nanosheet owing to the marginally twisted alignment between two neighboring layers, resulting in a highly localized flat band near the valence band maximum. Their bandgap depends on atomic stacking configurations, which gives a good interpretation for split moiré excitons using photoluminescence at 77 K. This work can benefit the development of twisted homo TMD moiré superlattices and could promote the profound research of twisted TMDs in the prospective field, such as strongly correlated physics and twistronics.

Organophosphorus Flame Retardant TCPP Induces Cellular Senescence in Normal Human Skin Keratinocytes: Implication for Skin Aging.

Tris (1-chloro-2-propyl) phosphate (TCPP) is one of the most frequently detected organophosphorus flames in the environment. Continuous daily exposure to TCPP may harm human skin. However, little is known about the adverse effects of TCPP on human skin. In this study, we first evaluated the detrimental effects and tried to uncover the underlying mechanisms of TCPP on human skin keratinocytes (HaCaT) after 24 h exposure. We found that TCPP caused a concentration-dependent decrease in HaCaT cell viability after exposure to 1.56-400 µg/mL for 24 h, with an IC50 of 275 µg/mL. TCPP also promoted the generation of intracellular reactive oxygen species (ROS) and triggered DNA damage, evidenced by an increase of phosphorylated histone H2A.X (γH2A.X) in the nucleus. Furthermore, the cell cycle was arrested at the G1 phase at 100 µg/mL by upregulation of the mRNA expression of p53 and p21 and downregulation of cyclin D1 and CDK4 expression. Additionally, both the senescence-associated-ß-galactosidase activity and related proinflammatory cytokine IL-1ß and IL-6 were elevated, indicating that TCPP exposure caused cellular senescence may be through the p53-dependent DNA damage signal pathway in HaCaT cells. Taken together, our data suggest that flame-retardant exposure may be a key precipitating factor for human skin aging.

E3 ubiquitin ligase NEURL3 promotes innate antiviral response through catalyzing K63-linked ubiquitination of IRF7.

Interferon regulatory factor 7 (IRF7), as the interferon-stimulated gene, maximally drives type I interferon (IFN) production. However, the mechanisms by which the biological function of IRF7 is regulated remain elusive. In this study, we found that IRF7 selectively interacted with the neuralized E3 ubiquitin-protein ligase 3 (NEURL3). In concomitant with IRF7 induction, NEURL3 is upregulated by NF-κB signaling in the late phase of viral infection. Moreover, NEURL3 augmented the host antiviral immune response through ubiquitinating IRF7. A mechanistic study revealed that NEURL3 triggered K63-linked poly-ubiquitination on IRF7 lysine 375, which in turn epigenetically enhanced the transcription of interferon-stimulated genes (ISGs) through disruption of the association of IRF7 with Histone Deacetylase 1 (HDAC1), consequently augmenting host antiviral immune response. Accordingly, Neurl3-/- mice produced less type I IFNs and exhibited increased susceptibility to viral infection. Taken together, our findings identify NEURL3 as an E3 ubiquitin ligase of IRF7 and shed new light on the positive regulation of IRF7 in host antiviral immune signaling.

Typical tumor immune microenvironment status determine prognosis in lung adenocarcinoma.

BACKGROUND: Immune cells, vital components of tumor microenvironment, regulate tumor survival and progression. Lung adenocarcinoma (LUAD), the tumor with the highest mortality rate worldwide, reconstitutes tumor immune microenvironment (TIME) to avoid immune destruction. Data have shown that TIME influences LUAD prognosis and predicts immunotherapeutic efficacy. The related information about the role of TIME's characteristics in LUAD is limited. METHODS: We performed unsupervised consensus clustering via machine-learning techniques to identify TIME clusters among 1906 patients and gathered survival data. The characteristics of TIME clusters of LUAD were visualized by multi-omics analysis, pseudo-time dynamic analysis, and enrichment analysis. TIME score model was constructed by principal component analysis. Comprehensive analysis and validation were conducted to test the prognostic efficacy and immunotherapeutic response of TIME score. RESULTS: TIME clusters (A, B and C) were constructed and exhibited different immune infiltration states. Multi-omics analyses included significant mutated genes (SMG), copy number variation (CNV) and cancer stemness that were significantly different among the three clusters. TIME cluster A had a lower SMG, lower CNV, and lower stemness but a higher immune infiltration level compared to TIME clusters B and C. TIME score showed that patients in low TIME score group had higher overall survival rates, higher immune infiltration level and high expression of immune checkpoints. In validation cohorts, low TIME score subgroup had better drug sensitivity and favorable immunotherapeutic response. CONCLUSION: We constructed a stable model of LUAD immune microenvironment characteristics that may improve the prognostic accuracy of patients, provide improved explanations of LUAD responses to immunotherapy, and provide new strategies for LUAD treatment.

Electronic Properties and Carrier Dynamics at the Alloy Interfaces of WS2x Se2-2x Spiral Nanosheets.

Electronic properties at the interfaces between different-composition domains of 2D-alloys are key for their optical, electronic, and optoelectronic applications. Understanding the interfacial electronic structures and carrier dynamics is essential for designing and fabricating devices that use these alloys. Here, WS2x Se2-2x spiral nanosheets are prepared using the physical vapor deposition method, and the nonlinear optical and electronic properties, as well as the carrier dynamics at the interfaces between the WS and WSe domains, are studied. Second-harmonic generation tests demonstrate that these nanosheets exhibit a very strong layer-dependent nonlinear optical effect. Atomic-resolution scanning tunneling microscopy (STM) and spectroscopy (STS) measurements reveal that S and Se atoms are non-uniformly distributed, forming WS domains, WSe domains, and defect-related areas. Atomic STM images and STS maps reveal enhanced local density of states by electron scattering at the WS/WSe interfaces, providing a detailed nanoscale interpretation of the S/Se-ratio-dependent lifetimes observed in pump-probe spectroscopy measurements. This work provides valuable interfacial characterization of 2D-alloy materials, using state-of-the-art methods with high temporal and spatial resolutions. The obtained insights are likely to be useful for prospective applications.

Glutathione peroxidase 4-dependent glutathione high-consumption drives acquired platinum chemoresistance in lung cancer-derived brain metastasis.

BACKGROUND: Platinum-based chemotherapy is effective in inducing shrinkage of primary lung cancer lesions; however, it shows finite therapeutic efficacy in patients suffering from brain metastasis (BM). The intrinsic changes of BM cells, which contribute to the poor results remain unknown. METHODS: Platinum drug-sensitivity was assessed by utilizing a preclinical BM model of PC9 lung adenocarcinoma cells in vitro and in vivo. High consumption of glutathione (GSH) and two associated upregulated proteins (GPX4 and GSTM1) in BM were identified by integrated metabolomics and proteomics in cell lines and verified by clinical serum sample. Gain-of-function and rescue experiments were implemented to reveal the impact and mechanism of GPX4 and GSTM1 on the chemosensitivity in BM. The interaction between GPX4 and GSTM1 was examined by immunoblotting and immunoprecipitation. The mechanism of upregulation of GPX4 was further uncovered by luciferase reporter assay, immunoprecipitation, and electrophoretic mobility shift assay. RESULTS: The derivative brain metastatic subpopulations (PC9-BrMs) of parental cells PC9 developed obvious resistance to platinum. Radically altered profiles of BM metabolism and protein expression compared with primary lung cancer cells were described and GPX4 and GSTM1 were identified as being responsible for the high consumption of GSH, leading to decreased chemosensitivity by negatively regulating ferroptosis. Besides, GSTM1 was found regulated by GPX4, which was transcriptionally activated by the Wnt/NR2F2 signaling axis in BM. CONCLUSIONS: Collectively, our findings demonstrated that Wnt/NR2F2/GPX4 promoted acquired chemoresistance by suppressing ferroptosis with high consumption of GSH. GPX4 inhibitor was found to augment the anticancer effect of platinum drugs in lung cancer BM, providing novel strategies for lung cancer patients with BM.

Paradoxical effects of arsenic in the lungs.

High levels (> 100 ug/L) of arsenic are known to cause lung cancer; however, whether low (≤ 10 ug/L) and medium (10 to 100 ug/L) doses of arsenic will cause lung cancer or other lung diseases, and whether arsenic has dose-dependent or threshold effects, remains unknown. Summarizing the results of previous studies, we infer that low- and medium-concentration arsenic cause lung diseases in a dose-dependent manner. Arsenic trioxide (ATO) is recognized as a chemotherapeutic drug for acute promyelocytic leukemia (APL), also having a significant effect on lung cancer. The anti-lung cancer mechanisms of ATO include inhibition of proliferation, promotion of apoptosis, anti-angiogenesis, and inhibition of tumor metastasis. In this review, we summarized the role of arsenic in lung disease from both pathogenic and therapeutic perspectives. Understanding the paradoxical effects of arsenic in the lungs may provide some ideas for further research on the occurrence and treatment of lung diseases.

Identification of differentially expressed genes-related prognostic risk model for survival prediction in breast carcinoma patients.

Since the imbalance of gene expression has been demonstrated to tightly related to breast cancer (BRCA) genesis and growth, common genes expressed of BRCA were screened to explore the essence in-between. In current work, most common differentially expressed genes (DEGs) in various subtypes of BRCA were identified. Functional enrichment analysis illustrated the driving factor of deactivation of the cell cycle and the oocyte meiosis, which critically triggers the development of BRCA. Herein, we constructed a 12-gene prognostic risk model relative to differential gene expression. Subsequently, the K-M curves, analysis on time-ROC curve and Cox regression were performed to assess this risk model by determining the respective prognostic value, and the prediction performance were ascertained for both training and validation cohorts. In addition, multivariate Cox regression was analysed to reveal the independence between risk score and prognostic stage, and the accuracy and sensitivity of prognosis are particularly improved after clinical indicators are included into the analysis. In summary, this study offers novel insights into the imbalance of gene expression within BRCA, and highlights 12 selected genes associated with patient prognosis. The risk model can help individualize treatment for patients at different risks, and propose precise strategies and treatments for BRCA therapy.

Manganese nanodepot augments host immune response against coronavirus.

Interferon (IFN) responses are central to host defense against coronavirus and other virus infections. Manganese (Mn) is capable of inducing IFN production, but its applications are limited by nonspecific distributions and neurotoxicity. Here, we exploit chemical engineering strategy to fabricate a nanodepot of manganese (nanoMn) based on Mn2+. Compared with free Mn2+, nanoMn enhances cellular uptake and persistent release of Mn2+ in a pH-sensitive manner, thus strengthening IFN response and eliciting broad-spectrum antiviral effects in vitro and in vivo. Preferentially phagocytosed by macrophages, nanoMn promotes M1 macrophage polarization and recruits monocytes into inflammatory foci, eventually augmenting antiviral immunity and ameliorating coronavirus-induced tissue damage. Besides, nanoMn can also potentiate the development of virus-specific memory T cells and host adaptive immunity through facilitating antigen presentation, suggesting its potential as a vaccine adjuvant. Pharmacokinetic and safety evaluations uncover that nanoMn treatment hardly induces neuroinflammation through limiting neuronal accumulation of manganese. Therefore, nanoMn offers a simple, safe, and robust nanoparticle-based strategy against coronavirus. Electronic Supplementary Material: Supplementary material (RNA-seq data analysis, IFN and ISGs examination, in vitro viral infection, flow cytometry, ICP-MS, DHE staining, and detection of inflammatory factors) is available in the online version of this article at 10.1007/s12274-020-3243-5.

Identification of novel Lynch syndrome mutations in Chinese patients with endometriod endometrial cancer.

Objective: Lynch syndrome (LS) predisposes patients to early onset endometrioid endometrial cancer (EEC). However, little is known about LS-related EEC in the Chinese population. The aim of this study was to investigate the prevalence of LS and to identify the specific variants of LS in Chinese patients with EEC. Methods: We applied universal immunohistochemistry screening to detect the expression of mismatch repair (MMR) proteins, which was followed by MLH1 methylation analysis to identify suspected LS cases, next-generation sequencing (NGS) to confirm LS, and microsatellite instability (MSI) analysis to verify LS. Results: We collected 211 samples with EEC. Twenty-seven (27/211, 12.8%) EEC cases had a loss of MMR protein expression. After MLH1 methylation analysis, 16 EEC cases were suggested to be associated with LS. Finally, through NGS and MSI analysis, we determined that 10 EEC (10/209, 4.78%) cases were associated with LS. Among those cases, 3 unreported mutations (1 frameshift and 2 nonsense) were identified. MSH6 c.597_597delC, found in 4 patients, is likely to be a founder mutation in China. Conclusions: We demonstrated the feasibility of a process for LS screening in Chinese patients with EEC, by using universal immunohistochemistry screening followed by MLH1 methylation analysis and confirmation through NGS and MSI analysis. The novel mutations identified in this study expand knowledge of LS.

Using Employment Data From a Medical University to Examine the Current Occupation Situation of Master's Graduates in Public Health and Preventive Medicine in China.

Aims: The purposes of this study are (1) to understand the current employment situation of master's graduates in Public Health and Preventive Medicine (PHPM) and (2) to provide evidence for career guidance and training of competent PHPM personnel. Methods: The master's graduates of the School of Public Health from the years 2014-2018 who majored in PHPM were chosen as research subjects. Questionnaires were distributed, and completed questionnaires were collected. The employment situation and characteristics of these graduates were analyzed based on the questionnaire data. Results: The employment rate of these graduates was 95.45%. They were employed mainly in hospitals, followed by colleges and centers for disease control and prevention. The initial salaries were low. Graduates whose jobs barely or not at all matched their areas of specialization were 23.64 or 6.36%, respectively. Nevertheless, the percentage of students who had remained with their jobs since graduation was 82.73%. A total of 40% of the graduates were neutral about or dissatisfied with their jobs. Furthermore, 29% of them claimed that they were undervalued by their employers. Last, but not least, graduates were encouraged to gain experience in creativity, organizational or management skills, social networking experience, and interpersonal and professional skills. Conclusion: Overall, the employment status of master's graduates in PHPM is good. Problems such as low initial salaries, jobs not matching graduates' areas of specialization, and feelings of being undervalued by employers were observed. It is necessary to improve employment outcomes by revising training models, formulating employment policies, and implementing training efforts.

Excellent Temperature-Control Based on Reversible Thermochromic Materials for Light-Driven Phase Change Materials System.

Light-driven phase change materials (PCMs) have received significant attention due to their capacity to convert visible light into thermal energy, storing it as latent heat. However, continuous photo-thermal conversion can cause the PCMs to reach high thermal equilibrium temperatures after phase transition. In our study, a novel light-driven phase change material system with temperature-control properties was constructed using a thermochromic compound. Thermochromic phase change materials (TC-PCMs) were prepared by introducing 2-anilino-6-dibutylamino-3-methylfluoran (ODB-2) and bisphenol A (BPA) into 1-hexadecanol (1-HD) in various proportions. Photo-thermal conversion performance was investigated with solar radiation (low power of 0.09 W/cm2) and a xenon lamp (at a high power of 0.14 W/cm2). The TC-PCMs showed a low equilibrium temperature due to variations in absorbance. Specifically, the temperature of TC-PCM180 (ODB-2, bisphenol A and 1-HD ratio 1:2:180) could stabilize at 54 °C approximately. TC-PCMs exhibited reversibility and repeatability after 20 irradiation and cooling cycles.

Lipidomic profiling of plasma samples from patients with mitochondrial disease.

Mitochondrial disease (MD) is a rare mitochondrial respiratory chain disorder with a high mortality and extremely challenging to treat. Although genomic, transcriptomic, and proteomic analyses have been performed to investigate the pathogenesis of MD, the role of metabolomics in MD, particularly of lipidomics remains unclear. This study was undertaken to identify potential lipid biomarkers of MD. An untargeted lipidomic approach was used to compare the plasma lipid metabolites in 20 MD patients and 20 controls through Liquid Chromatography coupled to Mass Spectrometry. Volcano plot analysis was performed to identify the different metabolites. Receiver operating characteristic (ROC) curves were constructed and the area under the ROC curves (AUC) was calculated to determine the potentially sensitive and specific biomarkers. A total of 41 lipids were significantly different in MD patients and controls. ROC curve analysis showed the top 5 AUC values of lipids (phosphatidylinositols 38:6, lysoPC 20:0, 19:0, 18:0, 17:0) are more than 0.99. Multivariate ROC curve based exploratory analysis showed the AUC of combination of top 5 lipids is 1, indicating they may be potentially sensitive and specific biomarkers for MD. We propose combination of these lipid species may be more valuable in predicting the development and progression of MD, and this will have important implications for the diagnosis and treatment of MD.

Lipidomic analysis of serum samples from migraine patients.

BACKGROUND: Migraine is a prevalent, disabling type of primary headache disorder associated with a high socioeconomic burden. The clinical management of migraine is challenging. This study was to identify potential serum lipidomic biomarkers of migraine. METHODS: The serum lipidomic profile of migraine sufferers was compared with healthy individuals using Liquid Chromatography coupled to Mass Spectrometry (LC-MS). Volcano plot analysis by Student's t-test was performed to identify the differential metabolites. Receiver operating characteristic (ROC) curves were constructed and the area under ROC curves (AUC) was calculated to evaluate whether the metabolites could be efficiently exploited for constructing a sensitive biomarker of migraine. RESULTS: A total of 29 serum metabolites from 4 classes of lipids including acylcarnitines, non-alpha-hydroxy-sphingosine ceramides (Cer_NSs), lysophosphatidylcholines (lysoPCs) and lysophosphatidylethanolamines (lysoPEs) were significantly different in migraine patients and controls. Of note, Cer_NSs were significantly elevated and lysoPEs were significantly decreased in migraine patients. LysoPE 18:1, lysoPE 18:2 and lysoPE 22:5 were found to be decreased in both positive and negative ion mode. Moreover, except for lysoPC 20:0, other lysoPCs were decreased in migraine patients. ROC curve analysis indicated that lysoPC 16:0 and lysoPC 20:0 are potential sensitive and specific biomarkers for migraine. CONCLUSION: LysoPC 16:0 and lysoPC 20:0 may be potential biomarkers for migraine. We suggest therapeutic management of these metabolites may be helpful in the prevention and treatment of migraine.

Low levels of serum serotonin and amino acids identified in migraine patients.

Migraine is a highly disabling primary headache associated with a high socioeconomic burden and a generally high prevalence. The clinical management of migraine remains a challenge. This study was undertaken to identify potential serum biomarkers of migraine. Using Liquid Chromatography coupled to Mass Spectrometry (LC-MS), the metabolomic profile of migraine was compared with healthy individuals. Principal component analysis (PCA) and Orthogonal partial least squares-discriminant analysis (orthoPLS-DA) showed the metabolomic profile of migraine is distinguishable from controls. Volcano plot analysis identified 10 serum metabolites significantly decreased during migraine. One of these was serotonin, and the other 9 were amino acids. Pathway analysis and enrichment analysis showed tryptophan metabolism (serotonin metabolism), arginine and proline metabolism, and aminoacyl-tRNA biosynthesis are the three most prominently altered pathways in migraine. ROC curve analysis indicated Glycyl-l-proline, N-Methyl-dl-Alanine and l-Methionine are potential sensitive and specific biomarkers for migraine. Our results show Glycyl-l-proline, N-Methyl-dl-Alanine and l-Methionine may be as specific or more specific for migraine than serotonin which is the traditional biomarker of migraine. We propose that therapeutic manipulation of these metabolites or metabolic pathways may be helpful in the prevention and treatment of migraine.

Immunostaining Study on the Expression of NF-κB, ER, and PR in Ovarian Serous Carcinoma.

In order to explore whether NF-κB activation correlates to the prognosis, chemoresistance, and sex hormone receptors status in ovarian serous carcinoma, we analyzed the expression of NF-κB, ER, and PR by immunohistochemistry in 72 cases of ovarian serous carcinoma, investigated the association among these markers, and evaluated their relations to clinicopathologic factors and prognosis. The positive rates were 88.9% for NF-κB cytoplasmic expression, 45.8% for NF-κB nuclear expression, 41.7% for ER, and 29.2% for PR. NF-κB nuclear expression was positively correlated with the 4th edition WHO grade (P=0.045) and tumor stage (P=0.001). NF-κB cytoplasmic expression was associated with preoperative serum CA125 level (P=0.015) and ascites (P=0.042). Neither cytoplasmic nor nuclear staining of NF-κB showed any association with survival. PR expression was correlated with tumor stage (P=0.023) and omental metastasis (P=0.022). Omental metastasis occurred more frequently in ER-/PR- tumors (P=0.009). No correlation between NF-κB expression and ER, PR expression was observed. In conclusion, in ovarian serous carcinoma, NF-κB nuclear expression correlated with the 4th edition WHO grade and PR was a favorable prognostic factor for ovarian serous carcinoma.